• E-mail
• Print
• Comment
• Font Size
• Digg
• del.icio.us
• Discuss article

Compliance and Persistence With Bisphosphonate Dosing Regimens Among Women With Postmenopausal Osteoporosis*

Posted on: Saturday, 15 October 2005, 03:00 CDT

By Cramer, Joyce A; Amonkar, Mayur M; Hebborn, Ansgar; Altman, Roy

ABSTRACT

Objective: Poor compliance and persistence with bisphosphonates is a concern in postmenopausal osteoporosis due to its negative impact on fracture risk and healthcare costs as well as quality of life. Reducing oral bisphosphonate dosing frequency is one measure available to increase therapy convenience and practicality, with the hope of improving compliance and persistence. This study compared compliance and persistence with weekly and daily bisphosphonate regimens for postmenopausal osteoporosis.

Methods: Administrative claims data (19972002) from 30 health plans were used to identify postmenopausal women (> 45 years) with osteoporosis, who had been newly prescribed a once-weekly (QW alendronate 35 mg or 70 mg) or once-daily (QD alendronate 5mg or 10mg or risedronate 5mg) bisphosphonate. QW and QD cohorts were followed for 12 months from initial prescription. Medication possession ratios (MPRs) measured refill compliance during follow- up. Persistence was calculated as the number of days from the initial prescription to a lapse of > 30 days after completion of the previous refill.

Results: Data were available for 2741 women (QW, N= 731, QD, N= 2010). QW users had significantly higher medication compliance than QD users (69.2% vs. 57.6% MPR, p < 0.0001). QW users persisted with therapy significantly longer than QD users (p < 0.0001) and had higher rates of retention on treatment at 12 months than QD users (44.2% QW; 31.7% QD). Dosing frequency was the strongest predictor of time to discontinuation (p <0.0001).

Conclusions: Postmenopausal women prescribed a weekly bisphosphonate had significantly better compliance and persistence than those taking more frequent, daily bisphosphonate doses. However, compliance and persistence rates for both regimens were suboptimal, suggesting that less frequent dosing intervals may provide an opportunity to further improve the consistent use of bisphosphonate therapy.

Introduction

Osteoporosis is associated with disruption in bone architecture, low bone mineral density (BMD) and an increased susceptibility to fractures1"3. This systemic skeletal disease is particularly prevalent in older postmenopausal women. With a mean age of menopause onset of approximately 50 years, women can now expect to live at risk of developing osteoporosis and fractures for one-third of their 80-year life span. The National Osteoporosis Foundation (NOF) estimated that in 2002 approximately 44 million people aged 50 years and over in the United States had either osteoporosis or low bone mass (osteopenia). This number is expected to exceed 52 million by the year 2010, rising to 61 million by 20204. Fractures associated with osteoporosis are a major cause of morbidity and mortality in postmenopausal women, and induce a high burden of pain and physical disability, with profound effects on quality of life5- 7. The annual direct costs to the US health care system associated with osteoporotic fractures totaled $13.8 billion in 1995, or $17.5 billion when indexed to 2002 prices7,8.

Bisphosphonates have become increasingly important in the management of postmenopausal osteoporosis because of their ability to reduce bone turnover, increase BMD, and decrease the incidence of fractures9. However, the potential or actual experience of side effects, the strict administration guidelines, and the dosing frequency of bisphosphonates may reduce the likelihood that patients will take the medication as directed (daily or weekly) over the long term. Regular use of bisphosphonate therapy is important to prevent fractures and chronic disability. Indeed, inadequate use of bisphosphonates has been shown to lead to inadequate reduction of biochemical markers of bone turnover10, insufficient increases in BMD11-13, and increased fracture risk13,14.

Previous studies provide evidence of poor persistence with bisphosphonate therapy. In a study of 401 postmenopausal women with osteoporosis or osteopenia, 13% of women prescribed oral daily alendronate did not even start treatment13. Among those that did start therapy, the probability of continuing was 49% at 1 year and 30% at 2 years. Discontinuation rates of 20% within 4 months and 17% within 6 months of starting weekly alendronate have been reported in two separate studies16,17. In a further study, Ettinger et al.18 reported that the rate of discontinuation of alendronate treatment increased linearly over time, with almost half of the women followed (46.1%) having discontinued therapy by the end of 10 months of follow-up. An analysis of the Canadian Database of Osteoporosis and Osteopenia (CANDOO) revealed that persistence with current bisphosphonates decreases over time, with 29.9% and 35.8% of 477 patients discontinuing treatment with daily alendronate after 1 and 2 years of treatment, respectively19. Studies have also shown that a significant proportion of patients who do persist with bisphosphonate treatment do not take an adequate amount of medication. In a study of 11 249 women with osteoporosis, 51% were poorly compliant with medication (including bisphosphonates)14.

One strategy to improve compliance is to increase patient convenience by decreasing the frequency of dosing regimens. Alendronate and risedronate, two currently marketed bisphosphonates, were initially introduced as once-daily formulations, but are now both available as once-weekly formulations. These formulations reduce the inconvenience of having to take the bisphosphonate in the morning, fasting, and remaining upright after dosing, to once weekly instead of daily. This is perceived as a major advantage for the weekly formulation by some patients20.

Despite evidence of poor compliance and persistence with bisphosphonate treatment, the impact of weekly versus daily dosing has not been extensively studied, or well documented, and the supposition of improved use with once-weekly compared with daily dosing has not been conclusively demonstrated. The current study examined comparative use, in terms of compliance and persistence, with these two dosing regimens by employing retrospective claims database analysis in a managed care population diagnosed with postmenopausal osteoporosis. This study also explored potential differences between younger (< 65 years) and older (> 65 years) women to determine whether age was a factor in bisphosphonate use.

Patients and methods

Data source

This study used a comprehensive, de-identified healthcare claims database that is representative of the insured non- institutionalized population in the USA to assess bisphosphonate usage. The database contains details of inpatient/outpatient medical and pharmacy claims and enrollment information on over 20 million lives. The data were collected from over 30 different healthcare plans serving members across nine census regions from January 1997 through July 2002. The health plans included health maintenance organizations (HMOs), point of service plans (POS), preferred provider organizations (PPOs) and indemnity plans. All patient identifiers are encrypted with a unique ID, which is used to track patients longitudinally, in accordance with the Health Insurance Portability and Accountability Act (HIPAA).

Patient selection and study design

The study population consisted of women new to bisphosphonate treatment with one or more medical claims for postmenopausal osteoporosis (ICD-9CM: 733.01) and one or more pharmacy claims for alendronate or risedronate (using National Drug Codes [NDC]) between July 1997 and June 2001. The first prescription for alendronate or risedronate was defined as the initial prescription. Subjects were required to have at least a 6-month run-in period without bisphosphonates before the index prescription and hence were considered to be bisphosphonate-nai've patients. To be eligible for inclusion in the study, subjects were also required to be over 45 years of age at the time of the initial prescription, and continuously enrolled in the health plan for 6 months before and 13 months after the filling of the initial prescription. Subjects meeting these inclusion criteria were then grouped into two cohorts: a daily cohort (alendronate 5 mg or 10 mg, or risedronate 5 mg, once daily) and a weekly cohort (alendronate 35mg or 70mg once weekly). Based on the timing of introduction of daily and weekly formulations, the majority of patients in the daily cohort were identified from January 1997 onwards while patients in the weekly cohort were available for follow up from November 2000 onwards. Patients who may have switched to another bisphosphonate (e.g., alendronate to risedronate) or regimen (e.g., daily to weekly) during follow-up were excluded from the analysis.

Outcome measures

The date of the initial pharmacy claim of bisphosphonates was assigned as the index date in the analysis. Each patient in the study cohort was followed for 13 months from the date of the index prescription with outcomes reported until the end of Month 12. The follow-up was continued to Month 13 to assess outcomes information (compliance and persistence) for any refills obtained in proximity to the 12-month outcomes follow-up period.

The outcome measures used for this study included: (1) persistence; (2) refill compliance; and (3) refill rates21-23. Persistence was defined as the time in days fromthe date of the first prescription of bisphosphonate to the run-out date of the last prescription in the treatment period. A treatment period was considered discontinued if the interval between two prescriptions exceeded 30 days after the run-out of the former prescription. Observations were censored if they exceeded the end of the follow- up window (12 months). Refill compliance was calculated using the Medication Possession Ratio (MPR). MPR was defined as the number of days supplied (from first to last prescription) within the 12-month follow-up period, divided by the length of follow-up, namely 365 days. Refill rates were determined from the number of prescription claims for the study cohorts over the 12-month follow-up period, including the initial claim.

Statistical analysis

Summary statistics for baseline characteristics (age, number of co-morbidities, and number of concomitant medications) of the two study cohorts were reported. The primary analysis included comparisons of the outcome measures between the two study cohorts. Descriptive statistics were used to compare persistence rates, time to discontinuation, MPR, and refill rates. Based on the type of outcome measure (ordinal or continuous data), chi-squares and f- tests were employed to identify any statistically significant differences between the two cohorts. The time to discontinuation of bisphosphonates from the first prescription was analyzed using a Kaplan-Meier plot with a log-rank test. MPRs were categorized into two groups for each of the cohorts: MPR ≥ 80% and ≤ 80%. The 80% cut-off was selected based on a previous study that demonstrated that patients having drug available to cover < 80% of the time are considered to be poorly compliant and have an increased risk of fracture14. A sub-group analysis was also performed for patients who were above 65 years of age. A Cox proportional hazards analysis was also performed to assess the impact of age, dosing frequency, number of baseline comorbidities (based on a simple count of unique ICD-9 codes, excluding the ICD-9 code for osteoporosis, 90 days prior to the initial bisphosphonate prescription), number of concomitant medications (based on a simple count of unique NDC drug codes, excluding bisphosphonate codes, 90 days prior to the initial bisphosphonate prescription), and type of health plan design on time to discontinuation with bisphosphonate therapy.

Results

Of the 2741 women who met the inclusion criteria, 2010 were prescribed daily alendronate (5 mg or lOmg) or risedronate (5mg) and 731 were prescribed weekly alendronate (35mg or 70mg), with 61.1% of the study participants in the younger age group (≤ 65 years). Baseline patient characteristics of the daily and weekly cohorts are listed in Table 1. The two cohorts were comparable in terms of number of co-morbidities and health plan design. However, the daily cohort had a greater proportion of patients over 65 years of age, while the weekly cohort was receiving a slightly greater number of concomitant medications.

Table 1. Baseline characteristics of the two study cohorts

Persistence

Treatment persistence (overall time to discontinuation) during the 12-month follow-up period was 196 days. As shown in Figure 1, treatment persistence differed significantly between the two cohorts. Persistence was significantly longer in once-weekly bisphosphonate users (226.8 days to discontinuation; 95% confidence interval [CI], 216.4-237.2; p < 0.0001) compared with oncedaily users (185.2 days to discontinuation; 95% CI, 178.9-191.4). At the end of 6 months, 58.1% of women on the once-weekly regimen and 44.6% of women on the once-daily regimen persisted with their therapies; at the end of 12 months, the respective percentages were 44.2% and 31.7%. Median duration of persistence was substantially higher in the once-weekly cohort than in the once-daily cohort (269 days; 95% CI, 213-325, vs. 134 days; 95% CI, 117-149, respectively).

Similar trends were observed in patients who were older than 65 years of age. Patients older than 65 years of age who were prescribed a once-daily regimen had significantly shorter persistence (173.7 days to discontinuation; 95% CI, 164.2-183.2; ρ = 0.015) compared with those who were prescribed the onceweekly regimen (198.5 days to discontinuation; 95% CI, 180.3- 216.6). At the end of 6 months, 50.4% of older patients on the weekly regimen persisted with their therapy compared with 39.9% of daily users. Persistence rates dropped to 34.4% and 27.9%, respectively, at the end of 12 months.

Figure 1. Persistence (time to discontinuation) in the daily and weekly cohorts, as measured by the percentage of patients remaining on therapy (Kaplan-Meier analysis). Persistence was statistically longer for the weekly compared with the daily cohort (p ≤ 0.0001). Median time to discontinuation for the weekly cohort was proportionally longer (269 days) than that for the daily cohort (133.5 days)

The results of the Cox proportional hazards model, which considered the covariates of dosing frequency, age, number of co- morbidities, number of concomitant medications and type of health plan are presented in Table 2. Controlling for other variables, dosing frequency was the strongest predictor of time to bisphosphonate therapy discontinuation, with patients on the weekly regimen 25% less likely to discontinue therapy compared to those on the daily regimen (hazard ratio [HR] = 0.7482, p < 0.0001). Other significant predictors were number of concomitant medications and type of health plan design. Patients with greater number of concomitant medications had an increased hazard of discontinuation (HR = 1.0216,p = 0.0096) while the patients with less restrictive health benefit coverage (indemnity, POS and PPOs) as compared to the HMOs had a lower hazard of discontinuation (HR = 0.8432, p = 0.0007) with bisphosphonate therapy. Increasing age and higher number of comorbidities, although non-significant, were trending towards increased hazards of discontinuation.

Medication possession ratio (MPR)

The mean MPR for the combined cohorts in this study was 60.6%. However, mean MPR was significantly higher in once-weekly users (69.2%; 95% CI, 66.771.8%; p < 0.0001) compared with once-daily users (57.6%; 95% CI, 56.0-59.2%; Figure 2). Similarly, when estimated for patients older than 65 years, onceweekly users had a significantly higher mean MPR (62.9%; 95% CI, 58.4-67.5%; p = 0.002) than oncedaily users (54.7%; 95% CI, 52.2-57.2%). The 80% MPR threshold of good refill compliance was achieved by a significantly higher percentage of patients in the weekly cohort (55.3%, p < 0.0001) compared with the daily cohort (40.4%). The corresponding percentages for women aged older than 65 years were 47.5% and 36.6%, respectively (p = 0.002).

Table 2. Multivariate Cox proportional hazards model predicting time to bisphosphonate therapy discontinuation

Figure 2. Refill compliance (mean Medication Possession Ratio [MPR] CI) for daily and weekly bisphosphonate cohorts. Weekly cohorts showed greater refill compliance than daily cohorts. When refill compliance was considered by patient age, older patients (> 65 years) showed lower compliance with either weekly or daily dosing than younger (≤ 65 years) patients (**p = 0.002; ***p ≤ 0.0001)

Refill rates

The mean number of refills (including the index fill) obtained by the once-daily cohort was significantly lower (5.80; 95% CI, 5.62- 5.98; p ≤ 0.0001) compared with the once-weekly cohort (7.32; 95% CI, 7.?υ7.65). Additionally, a significantly greater percentage of patients in the daily cohort (46.4%, ρ < 0.0001) had less than four prescription fills (index plus three refills) compared with those in the weekly cohort (31.3%). Similar results were observed in patients aged over 65 years, with patients in the daily cohort obtaining a mean of 5.30 fills (95% CI, 5.02-5.57; ρ = 0.005) compared with 6.14 (95% CI, 5.59-6.68) fills in the weekly cohort. A significantly greater percentage of patients aged over 65 years who were prescribed the once-daily regimen had filled less than four prescriptions (52.4%, p < 0.0001) compared with those who were prescribed the weekly regimen (42.2%).

Discussion

The results of this study demonstrate that less frequent dosing with bisphosphonates is associated with improved treatment compliance and persistence. Controlling for other factors, dosing frequency was the strongest predictor of persistence with bisphosphonate therapy. Patients on the once-weekly regimen had longer persistence, and higher refill compliance (MPR) and refill rates compared with patients on the oncedaily regimen. However, even with the weekly regimen, persistence, refill compliance and refill rates remained suboptimal. Less than half of patients on the weekly regimen and approximately one-third of those on the daily regimen persisted with their therapy at the end of 12 months. For patients older than 65 years, persistence rates were even lower (34.4% vs. 27.9%, respectively).

Bisphosphonate use and patient outcomes

The impact of suboptimal bisphosphonate usage on clinical (rate of bone turnover, BMD changes, fracture risk) and economic (healthcare utilization and costs) outcomes, although not assessed in the current study, has been demonstrated in other investigations. Analysis of the IMPACT study database of 2302 women with postmenopausal osteoporosis demonstrated that a clinically significant decrease (> 50%) in levels of biochemical markers of bone rsorption can be expected in more than 60% of patients who take their bisphosphonate treatment consistently compared with only 20% of poorly compliant patients10.

The link between inadequate use of bisphosphonates and adverse impact on BMD has been demonstrated in several studies11,12. A study of 176 previously untreated women with osteoporosis found that patients who took at least two-third\s of their bisphosphonate medication showed increases in BMD of 3.8% and 2.6% at the lumbar spine and hip, respectively12. These increases were significantly higher than the respective increases of 2.1% (p < 0.005) and 2.3% (p < 0.0056) in patients who were less compliant12. Similar findings from a questionnaire that included 240 patients showed that those taking medication achieved greater improvements in BMD (4.3% and 1.2% at the lumbar spine and hip, respectively), than those taking less medication (2.8% and 0.3%, respectively)11. The Canadian Database of Osteoporosis and Osteopenia (CANDOO) study of 1041 patients with osteoporosis treated in routine clinical care, also found increases in lumbar spine BMD that were significantly greater in patients who consistently took more than 80% bisphosphonate doses compared with those who did not13. Lumbar spine BMD increased by 6.5% (95% CI: 3.7-9.3%) from baseline in consistent users of bisphosphonate therapy after 3 years. The corresponding increase in BMD in inconsistent users was 3.2% (0.03-6.3%)13.

Previous studies have also demonstrated that patients who do not take adequate amounts of bisphosphonate therapy are at a greater risk of fracture. In one study of 11 249 women with osteoporosis, patients who were poorly compliant were at a significantly greater risk of fractures than patients who complied well (16% greater risk; 95% CI, 5-25%)14. This study also reported a significant association between poor compliance and economic outcomes, with poorly compliant patients significantly more likely to be hospitalized than compliant patients, resulting in a 14% increase in costs for medical services. In the CANDOO study13, there was a nonsignificant trend towards a 27% greater 10-year fracture risk among patients taking therapy inconsistently.

In the current study, compliance and persistence rates with both weekly and daily regimens were even lower for women aged over 65 years than those for all postmenopausal women. The need for treatment persistence among older women has also been noted for other postmenopausal therapy24,25. The impact of poor compliance and persistence on outcomes is likely to be even greater among older patients for a number of reasons; the increase in incidence of osteoporosis26 and fracture rate27 with age suggests a higher likelihood of poor therapeutic outcomes if elderly patients take inadequate medication. In addition, polypharmacy is more likely, due to the higher prevalence of other chronic conditions among older patients. For example, a survey of the US noninstitutionalized adult population indicated that 57% of persons aged ≥ 65 years use ≥ 5 different medications per week (23% using ≥ 5 prescription drugs) while 12% use ≥ 10 different medications28. The consequent complexity and frequency of the combined regimens is also likely to adversely affect bisphosphonate use and fracture risk, with possible consequences for all the comorbidities. The current study showed that increasing age, number of co-morbidities and number of concomitant medications were all associated with worse persistence.

Several factors not assessed in the current study may explain inadequate use of bisphosphonates, including adverse effects, intolerability, patient beliefs and attitudes, and physician involvement in patient care. However, the current study has demonstrated that dosing regimen is a key predictor for compliance and persistence, with greater use of weekly than daily bisphosphonate regimens. Nevertheless, both compliance and persistence rates still remain low and leave ample room for improvement. In view of the significant improvements in compliance and persistence seen after the introduction of weekly alendronate and risedronate, it is postulated that an even greater improvement may result from still less frequent dosing (e.g., monthly or quarterly), leading to improved therapy outcomes and more efficient use of healthcare resources. Any simplification of the regimen is likely to further minimize the potential or actual experience of side effects and the inconvenience of having to take the bisphosphonate in the morning, fasting, and remaining upright after dosing. Reducing dosing frequency has been shown to increase compliance and persistence rates in other therapeutic areas and conditions29-33. For example, a systematic review across a variety of treatments and diseases found dose-taking compliance increased with decreasing dose frequency from 51% for four-times daily dosing to 79% for once-daily dosing33. Pharmacy claims have also demonstrated good correlation with drug exposure34. However, certain limitations do exist when using data that are primarily collected for administrative purposes, as billing and coding errors may affect the data.

Pharmacy claims data, on which this study was based, have demonstrated good correlation with drug exposure34 and is a commonly used method to estimate compliance and persistence. However, certain limitations do exist when using data that are primarily collected for administrative purposes, as billing and coding errors may affect the data. Pharmacy claims are only an indirect measure of medication- taking behavior and the presence of a prescription claim does not necessarily imply that the medication was taken35,36. Other limitations of the study may include incorrect drug therapy initiation dates (if the prescriber provided drug samples or if the prescription was filled at a non-health plan pharmacy), lack of or minimal data on important variables such as previous fractures, other osteoporosis therapies and patient copay, and lack of control on any extraneous factors that may have impacted the outcome measures during the different time periods that the weekly and daily cohorts were observed (the once-weekly formulation was available after October 2000). Ideally, this study would have assessed other factors that may affect compliance and persistence rates, such as adverse effects, patient's beliefs and attitudes, and physician involvement in patient care, or direct monitoring of dosing37.

Conclusion

This study has demonstrated that postmenopausal women prescribed a weekly bisphosphonate regimen had significantly higher rates of compliance and longer persistence compared with those taking a more frequent, daily dosing regimen. However, rates for both regimens were less than desirable. Results indicate that less frequent bisphosphonate dosing is associated with increases in compliance and persistence rates, suggesting that the development of more convenient regimens and healthcare initiatives to enhance dose compliance and treatment persistence may provide an opportunity to further increase the therapeutic potential of bisphosphonates. This could be a particular advantage for older women, who are not only at greater risk of osteoporosis, but also were found to have lower compliance and persistence rates. Although some women may perceive the burden of taking a bisphosphonate to be greater than the actual risk of experiencing a fracture, this is most likely not the perspective of the payer, who will want to avoid fractures and associated healthcare resource utilization, particularly among elderly women. These data suggest the need for physicians to consider the potential advantages of less frequent, less burdensome dosing regimens when selecting treatment for osteoporosis in order to increase persistence with therapy.

Acknowledgements

Declaration of interest: This study was supported by GlaxoSmithKline and Hoffman-La Roche. J. A. Cramer and R. Altman are consultants to the sponsors; M. M. Amonkar and A. Hebborn are employees of the sponsors.

The authors thank Nittaya Suppapanya for statistical support.

* These data were presented at the International Society for Pharmacoeconomics and Outcomes Research meeting, Hamburg, DE, November 2004

References

1. Consensus Development Conference. Prophylaxis and treatment of osteoporosis. Am J Med 1991;90:107-10

2. Melton LJ III. How many women have osteoporosis now? J Bone Miner Res 1995; 10:175-7

3. Kanis JA, Geusens P, Christiansen C. Guidelines for clinical trials in osteoporosis: a position paper of the European Foundation for Osteoporosis and Bone Disease. Osteoporosis Int 1991;1:182-8

4. National Osteoporosis Foundation. America's bone health: the state of osteoporosis and low bone mass in our nation. National Osteoporosis Foundation, 2002

5. Woolf AD, PflegerB. Burden of major musculoskeletal conditions. Bull World Health Organ 2003;81:646-56

6. Johnell O, Kanis JA. An estimate of the worldwide prevalence, mortality and disability associated with hip fracture. Osteoporos Int 2004;15:897-902

7. Ray NF, Chan JK, Thamer M, et al. Medical expenditures for the treatment of osteoporotic fractures in the United States in 1995: report from the National Osteoporosis Foundation. J Bone Miner Res 1997;12:24-35

8. Melton LJ III. Adverse outcomes of osteoporotic fractures in the general population. J Bone Miner Res 2003;18:1139-41

9. Hodgson SF, Watts NB, Bilezikian JP, et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the prevention and treatment of postmenopausal osteoporosis: 2001 edition, with selected updates for 2003. Endocr Pract 2004;9:544-64

10. Eastell R, Garnero P, Vrijens B, et al. Influence of patient compliance with risedronate therapy on bone turnover marker and bone mineral density response: the IMPACT study. Calcif Tissue Int 2003;72:297

11. Finigan J, Bainbridge PR, Eastell R. Adherence to osteoporosis therapies. Osteoporos Int 2001;12:S48-9 [abstract P110)]

12. Yood RA, Emani S, Reed JI, et al. Compliance with pharmacologie therapy for osteoporosis. Osteoporos Int 2003; 14:965- 8

13. Sebaldt RJ, Shane LG, Pham B, et al. Longer term effectiveness outcomes of noncompliance and nonpersistence with daily regimen bisphosphonate therapy in patients with osteoporo\sis treated in tertiary specialist care. Osteoporos Int 2004;15(Suppl 1): S107 [abstract P391 SA]

14. Caro JJ, Ishak KJ, Huybrechts KF, et al. The impact of compliance with osteoporosis therapy on fracture rates in actual practice. Osteoporos Int 2004;15:1003-8

15. Lombas C, Hakim C, Zanchetta JR. Compliance with alendronate treatment in an osteoporosis clinic. J Bone Miner Res 2001;15: S529 [abstract M406]

16. Negri AL. Short-term compliance with alendronate 70 mg in patients with osteoporosis: The ECMO Trial. Bone 2003;23(Suppl):P487 [abstract]

17. Bandeira F, Kayath M, Marques-Neto J, et al. Patients' clinical features and compliance associated with raloxifine or alendronate after a six-month observational Brazilian study. J Bone Miner Res 2003;18(Suppl 2):S379 [abstract M352]

18. Ettinger B, Pressman AR, Schein J, et al. Alendronate use among 812 women: prevalence of gastrointestinal complaints, non- compliance with patient instructions and discontinuation. J Managed Care Pharm 1998:4:488-92

19. Papaioannou A, Ioannidis G, Adachi JD, et al. Adherence to bisphosphonates and hormone replacement therapy in a tertiary care setting of patients in the CANDOO database. Osteoporos Int2003;14:808-13

20. Simon JA, Lewiecki EM, Smith ME, et al. Patient preference for once-weekly alendronate 70 mg versus once-daily alendronate 10mg: a multicenter, randomised, open-label, crossover study. ClinTher 2002;24:1871-86

21. Catalan VS, LeLorier J. Predictors of long-term persistence on statins in a subsidized clinical population. Value Health 2000;3:417-26

22. Breekveldt-Postma NS, Herings R. Persistence with antihypertensives related to formulation: the case of nifedipine. Ann Pharmacother 2005;39:237-42

23. Stoloff SW, Stempel DA, Meyer J, et al. Improved refill persistence with fluticasone propionate and salmeterol in a single inhaler compared with other controller therapies. J Allergy Clin Immunol 2004;113:245-51

24. Schiff I, Rebar RW, Cramer JA, et al. Achieving long-term continuance of menopausal ERT/HRT: consensus opinion of the North American Menopause Society. Menopause 1998;5:69-76

25. Cramer JA. Enhancing patient compliance in the elderly. Role of packaging aids and monitoring. Drugs Aging 1998; 12:7-15

26. Prestwood KM. Osteoporosis: up-to-date strategies for prevention and treatment. Geriatrics 1997:52:92-4,97-8

27. Gallagher JC. Pathophysiology of osteoporosis. Semin Nephrol 1992;12:109-15

28. Kaufman DW, Kelly JP, Rosenberg L, et al. Recent patterns of medication use in the ambulatory adult population of the United States: the Slone Survey. JAMA 2002;287: 337-44

29. Cramer JA, Mattson RH, Prevey ML, et al. How often is medication taken as prescribed? A novel assessment technique. JAMA1989;261:3273-7

30. Cramer JA, Rosenheck R. Compliance with medication regimens for mental and physical disorders. Psychiatr Serv 1998;49: 196-201

31. Cramer JA. Consequences of intermittent treatment for hypertension: The case for medication compliance and persistence. Am J Managed Care 1998;4:1563-8

32. Venturini F, Nichol MB, Sung JC, et al. Compliance with sulfonylureas in a health maintenance organization: a pharmacy record-based study. Ann Pharmacother 1999)33:281-8

33. Claxton AJ, Cramer J, Pierce C. A systematic review of the associations between dose regimens and medication compliance. Clin Ther 2001;23:1296-310

34. Steiner JF, Koepsell TD, Fihn SD, et al. A general method of compliance assessment using centralized pharmacy records. Description and validation. Med Care 1988)26:814-23

35. Farmer KC. Methods for measuring and monitoring medication regimen adherence in clinical trials and clinical practice. CHn Ther 1999)21:1074-90

36. Steiner JF, Prochazka AV. The assessment of refill compliance using pharmacy records: Methods, validity, and application. J Clin Epidemiol 1997)50:105-16

37. Cramer JA. Overview of methods to measure and enhance patient compliance. In: Cramer JA, Spilker B, editors. Patient Compliance in Medical Practice and Clinical Trials. New York, NY: Raven Press, 1991, pp.3-10

Joyce A. Cramer(a), Mayur M. Amonkar(b), Ansgar Hebborn(c) and Roy Altman(d)

a Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA

b GlaxoSmithK/ine, Collegeville, PA, USA

c Hoffmann-La Roche, Nutley, NJ, USA

d School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA

Address for correspondence: Joyce A. Cramer, Department of Psychiatry, Yale University School of Medicine, 950 Campbell Avenue (G7E), West Haven, CT 06516-2770, USA. Tel.: +1-203-937-3894, Fax: +1-203-937-3468; email: joyce.cramer@yale.edu

Key words: Bisphosphonates - Compliance - Persistence - Postmenopausal osteoporosis

Copyright Librapharm Sep 2005

Source: Current Medical Research and Opinion

More News in this Category